Residual inflammatory risk associated with IL-18 and IL-6 after successful IL-1b inhibition with canakinumab: further rationale for the development of targeted anti-cytokine therapies for the treatment of atherothrombosis.
Trial Reference
Ridker PM, MacFadyen JG, Thuren T, Libby P. Residual inflammatory risk associated with interleukin-18 and interleukin-6 after successful interleukin-1b inhibition with canakinumab: further rationale for the development of targeted anti-cytokine therapies for the treatment of atherothrombosis. Eur Heart J. 2020 Jun 14;41(23):2153-2163. doi: 10.1093/eurheartj/ehz542.
Expert Comment
Pablo Avanzas, MD, PhD, FESC
Professor of Medicine, University of Oviedo, Oviedo, Spain
Background
The Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) established that targeting inflammation with interleukin-1β (IL-1β) inhibition can significantly reduce cardiovascular (CV) event rates in the absence of any beneficial effects on cholesterol. Yet, CANTOS participants treated with both high-intensity statins and canakinumab remain at considerable risk for recurrent CV events. The aim of this study was to assess whether both interleukin-18 (IL-18, which like IL-1β requires the NLRP3 inflammasome for activation) and interleukin-6 (IL-6, a pro-inflammatory cytokine downstream of IL-1) may contribute to the recurrent events that occur even on canakinumab therapy, and thus represent novel targets for treating atherothrombosis.
Plasma samples from 4848 stable post-myocardial infarction patients who were assigned to active IL-1β inhibition or placebo within CANTOS underwent measurement of IL-18 and IL-6 both before and after initiation of canakinumab using validated ELISA. All participants were followed over a median 3.7-year period (maximum 5 years) for recurrent major adverse cardiovascular events (MACE) and for all-cause mortality. Compared to placebo, canakinumab significantly reduced IL-6 levels in a dose-dependent manner yielding placebo-subtracted median percent reductions in IL-6 at 3 months of 24.8%, 36.3%, and 43.2% for the 50, 150, and 300 mg doses, respectively (all P-values <0.001). By contrast, no dose of canakinumab significantly altered IL-18 levels measured at 3 months (all effects <1%, all P-values > 0.05). Yet, despite these differential plasma effects, either baseline and on-treatment levels of IL-18 or IL-6 associated with rates of future CV events. For example, for MACE, each tertile increase in IL-18 measured 3 months after canakinumab initiation associated with a 15% increase in risk [95% confidence interval (CI) 3–29%, P = 0.016], while each tertile increase in IL-6 measured 3 months after canakinumab initiation associated with a 42% increase in risk (95% CI 26–59%, P < 0.0001). Similar effects were observed for MACE-plus, CV death, all-cause mortality, and the for the combination endpoint of all vascular events inclusive of revascularization procedures and hospitalization for congestive heart failure. In baseline as well as on-treatment analyses, risks were highest among those with the highest levels of both IL-18 and IL-6.
Comment
Since its publication, the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS) was perceived as the final proof of concept of more than two decades of research, pointing to atherosclerosis as a complex inflammatory disorder involving both adaptive and innate immunity. In addition to this, CANTOS represented the first step in the endorsement of anti-inflammatory therapies on top of intense lipid lowering in the prevention and treatment of cardiovascular disease (CVD).
The main findings of this CANTOS sub study are:
- IL-1β inhibition with canakinumab significantly reduces plasma levels of IL-6 but not IL-18, yet that baseline and on-treatment levels of either IL-6 or IL-18 predict risk of recurrent CV events. The current analyses also indicate that residual inflammatory risk after IL-1β inhibition associated with IL-6 exceeds in absolute magnitude that associated with IL-18. In addition, these analyses indicate that the effects of IL-6 and IL-18 on CV risk are additive to each other, both before and after initiation of IL-1β inhibition.
- The observation in these data that residual inflammatory risk both before and after treatment with canakinumab is larger in absolute magnitude for IL-6 than for IL-18 provides support for the potential use of anti-cytokine therapies that inhibit IL-6 signalling for atherothrombosis.
- The observation here that the magnitude of effect of IL-6 appears to be larger than that of IL-18 may importantly reflect issues of biologic amplification. Either IL-1 or IL-18 can induce IL-6, providing an amplification step that may contribute to the greater magnitude of the relationship between recurrent events and IL-6 and its upstream inducer IL-18. As such, agents that target the upstream NLRP3 inflammasome should reduce both IL-1β and IL-18, and as a biologic consequence, downstream IL-6.
In conclusion, there remains substantial residual inflammatory risk related to both IL-18 and IL-6 after IL-1β inhibition with canakinumab. These data have importance not only for understanding the mechanisms of inflammation inhibition associated with canakinumab, but also for the future development of novel anti-inflammatory agents targeting atherothrombosis. The results of this study definitely support further pharmacologic development of therapies for atherothrombosis that target IL-18 or IL-6 signalling, or that can simultaneously inhibit both IL-1β and IL-18 (such as NLRP3 inflammasome inhibitors).